Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.
Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts.
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DOI：
10.15252/emmm.201404914
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发表时间：
2015-09
影响因子：
11.1
通讯作者：
Peeper DS
中科院分区：
文献类型：
--
作者：
Kemper K;Krijgsman O;Cornelissen-Steijger P;Shahrabi A;Weeber F;Song JY;Kuilman T;Vis DJ;Wessels LF;Voest EE;Schumacher TN;Blank CU;Adams DJ;Haanen JB;Peeper DS
靶向抑制剂的开发，如维莫拉非尼，极大地改善了BRAFV600E转移性黑色素瘤的临床结果。然而，对这类化合物的耐药性是一个可怕的问题。利用全外显子组测序和功能分析，我们研究了一例携带多重耐药转移瘤的黑色素瘤患者对维莫拉非尼耐药的性质和多效性。抗性是由过多的机制引起的，所有这些机制都重新激活了MAPK途径。除了BRAFV600E的三个独立扩增和一个异常形式外，我们还在MEK1中发现了一个新的激活插入。这种MEK1T55delinsRT突变可以追溯到治疗前的一小部分损害，不仅提供了对维莫拉非尼的保护，而且促进了移植黑色素瘤的局部侵袭。对来自治疗难治性转移瘤的患者来源的异种移植(PDX)的分析表明，在一个转移瘤内存在多种耐药机制。这种异质性，包括肿瘤内和肿瘤内，导致在PDX中不能完全捕获在患者中观察到的耐药机制。总而言之，维莫拉非尼在单个患者中的耐药性可以通过不同的事件来建立，这些事件可能是预先存在的。此外，我们的结果表明，PDX可能不会像患者的黑色素瘤那样具有完全的遗传异质性。
The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAFV600E metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient’s melanoma.